B-cell lymphomas are a common complication of AIDS, and many of these lymphomas contain the EBV genome. Unfortunately, there is currently no widely available small animal model for examining EBV/HIV pathogenesis, and testing potential novel therapies, in the context of an intact immune system. Recently, however, it was shown that injection of CD34+ human cord blood cells into irradiated newborn Rag2- /gammaC- double knock-out mice allows reconstitution of the entire human immune system, including the development of B-cell, T-cell, and natural killer cell lineages (63). Furthermore, when immune- reconstituted Rag2-/gammaC- double knock-out mice are infected with EBV, they develop an appropriate cytotoxic T cell response that controls EBV infection and prevents subsequent lymphoma development (63). In this grant, we propose to use this new mouse model to examine the importance of specific human immune cell subtypes, and HIV co-infection, in the pathogenesis of AIDS-related EBV-induced lymphomas. Our specific aims are to 1) define the natural history of wild-type EBV infection in rag2- /gammaC-double knock-out mice reconstituted with human hematopoietic cells, determining the types of cells infected during primary versus chronic infection, and the viral gene expression pattern in each cell type; and 2) determine if depletion of specific T-cell subsets, depletion of natural killer cells, immunosuppressant drugs or HIV co- infection promote the development of B-cell lymphomas following EBV infection in rag2-/gammaC- double knockout mice reconstituted with the human immune system. [unreadable] [unreadable] [unreadable]